Abstract
Over recent years hyperpolarization by dissolution dynamic nuclear polarization has become an established technique for studying metabolism in vivo in animal models. Temporal signal plots obtained from the injected metabolite and daughter products, e.g. pyruvate and lactate, can be fitted to compartmental models to estimate kinetic rate constants. Modeling and physiological parameter estimation can be made more robust by consistent and reproducible injections through automation. An injection system previously developed by us was limited in the injectable volume to between 0.6 and 2.4ml and injection was delayed due to a required syringe filling step. An improved MR-compatible injector system has been developed that measures the pH of injected substrate, uses flow control to reduce dead volume within the injection cannula and can be operated over a larger volume range. The delay time to injection has been minimized by removing the syringe filling step by use of a peristaltic pump. For 100μl to 10.000ml, the volume range typically used for mice to rabbits, the average delivered volume was 97.8% of the demand volume. The standard deviation of delivered volumes was 7μl for 100μl and 20μl for 10.000ml demand volumes (mean S.D. was 9 ul in this range). In three repeat injections through a fixed 0.96mm O.D. tube the coefficient of variation for the area under the curve was 2%. For in vivo injections of hyperpolarized pyruvate in tumor-bearing rats, signal was first detected in the input femoral vein cannula at 3–4s post-injection trigger signal and at 9–12s in tumor tissue. The pH of the injected pyruvate was 7.1±0.3 (mean±S.D., n=10). For small injection volumes, e.g. less than 100μl, the internal diameter of the tubing contained within the peristaltic pump could be reduced to improve accuracy. Larger injection volumes are limited only by the size of the receiving vessel connected to the pump.
Highlights
Dissolution dynamic nuclear polarization [1] has afforded a step change in the available MR signal for nuclei such as 13C
We have shown previously that a reproducible injection/withdrawal system can be used to provide a consistent arterial input function for compartmental modelling and extraction of physiological parameters [5]
The receive vessel contained a predetermined aliquot of 2.0 M sodium hydroxide solution (Sigma Aldrich) required to neutralize the pyruvic acid (PA) and 2.0 ml HEPES/EDTA buffer solution to ensure that the receive vessel outlet pipe was submerged
Summary
Dissolution dynamic nuclear polarization (dDNP) [1] has afforded a step change in the available MR signal for nuclei such as 13C. The hyperpolarized signals are acquired rapidly to provide spectroscopic information on the conversion of the injected substrate to its metabolites within the tissue of interest and has been applied to the imaging of tumors [2] and their response to drug treatment [3]. A previously developed automated injection system [6] provided reproducible injection volumes, rates and timing for animal studies [5]. An adjustable screw was fitted to the rear of the peristaltic pump to vary the degree of compression exerted by the pump housing on the tubing contained within the peristaltic pump This was done in order to reduce the torque requirement for the drive shaft and stepper motor. Control of the stepper motor and injection system was realized by an Arduino microcontroller, as described below
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